Triple Therapy / Combination Therapy for Rheumatoid Arthritis | Rheumatoid Arthritis Warrior

Triple Therapy / Combination Therapy for Rheumatoid Arthritis

Treatments for Rheumatoid Arthritis

shadow of lizard in windowIn the past few decades, Rheumatoid Arthritis has been treated with therapies designed for other diseases. It was not always clear how these drugs treated Rheumatoid Arthritis / Rheumatoid Disease, but they were found to reduce immune activity in various ways. Because researchers recognized certain drugs could slow or modify progression of disease, they called them disease modifying anti-rheumatic drugs (DMARDs) – listed here. Sometimes, stronger immune suppressants, such as those used to reduce organ transplant rejection, are used in Rheumatoid patients.

Biologicals or biologic DMARDs used to treat Rheumatoid Disease (RD) were developed to specifically target certain aspects of immune function that are significant to Rheumatoid disease activity. As more is learned about immune function, it becomes possible to “interrupt” certain pathways or signals. For some people, these treatments reduce disease activity significantly.

Here’s a list of biologic DMARDs currently approved in the U.S. for treating RD.

Note that a new abbreviation for biologic DMARD is being used: bDMARD.

Combination therapy: Rheumatoid Arthritis treatments taken jointly 😉

Biologics like Enbrel, Humira, Actemra, Orencia and others are usually used in combination with a conventional DMARD like methotrexate. Combination treatments are more effective at reducing disease activity, and biologics were tested in clinical trials in conjunction with methotrexate. Methotrexate is believed to help reduce the tendency to produce antibodies against Biologics.

Triple therapy with DMARDs

In recent years, triple therapy has been investigated as an alternative to more expensive biologics. Triple therapy refers to a combination of three non-biologic DMARDs, most frequently sulfasalazine, hydroxychloroquine, and methotrexate. Other DMARDs can be used based on what medications patients can tolerate. Combining biologics is not approved by the FDA, or done in usual practice, but some investigation is being done. Of course any combination therapy including triple therapy reduces immune function, so people treated with these methods should make their doctors aware of every medication they use, and practice preventive first aid.

Does it work?

Triple therapy is not inferior to Biologic combination therapy

A study by O’Dell et al. published in June, Therapies for Active Rheumatoid Arthritis after Methotrexate Failure, compared triple therapy head to head with Enbrel (etanercept) and methotrexate.[1] They found the clinical benefit of triple therapy (sulfasalazine, hydroxychloroquine, and methotrexate) was “noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy.”

Clinical benefit was compared with various scores of symptom improvement and joint damage (see partial list below). Although the Enbrel combination scores were better in some cases, the investigators determined that as a whole, triple therapy was statistically noninferior and would be an option to use before more expensive bDMARDs are tried.

What do you think? Here’s my reaction

Studies have shown that biologic DMARDs, when effective, reduce damage and disease progression. They address systemic RD inflammation that causes changes in bone metabolism, evidenced by both localized erosions and generalized bone loss (osteoporosis).[2] By reducing systemic inflammation, biologics also reduce the risk of premature death in RD (by 25% in one study).[3]

Successful treatment of Rheumatoid Disease must involve both symptom improvement and reduction of long-term disease progression or damage of the musculoskeletal system. And, RD treatments should also address matters related to systemic disease that are not frequently measured at this point. That is the definition of successful treatment in my book.

I’m sure I’ll hear more at the ACR Annual Scientific Meeting about both the benefits of triple therapy and reasons newer treatments are better. I’ll let you know.

NOTE: Some scores reported in the study. TT is triple therapy. Enbrel was combined with mtx.

Health Assessment Questionnaire II score

At 24wk TT mean change −0.44±0.77 Enbrel mean change −0.51±0.84; P value 0.46
At 48wk TT mean change −0.46±0.82 Enbrel mean change −0.64±0.78; P value 0.06

Modified Sharp score

At 24wk TT mean change 0.42±1.91; Enbrel mean change 0.003±3.62; P value: 0.20
At 48wk TT mean change 0.54±1.93; Enbrel mean change 0.29±3.32; P value: 0.43


At 24wk TT mean change 0.23±1.32; Enbrel mean change −0.03±1.44; P value: 0.10
At 48wk TT mean change 0.29±1.35; Enbrel mean change 0.08±1.48; P value: 0.21

Joint-space narrowing

At 24wk TT mean change 0.19±1.25; Enbrel mean change 0.03±2.47; P value: 0.45
At 48wk TT mean change 0.25±1.18; Enbrel mean change 0.21±2.09; P value: 0.83

Recommended reading

1 O’Dell JR, Mikuls TR, Taylor TH, Ahluwalia V, Brophy M, Warren SR, Lew RA, Cannella AC, Kunkel G, Phibbs CS, Anis AH, Leatherman S, Keystone E; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med [Internet]. 2013 Jul 25 [cited 2013 Oct 19];369(4):307-18. doi: 10.1056/NEJMoa1303006. Available from:
2 Corrado A, Neve A, Maruotti N, Cantatore FP. Bone effects of biologic drugs in rheumatoid arthritis. Clinical and Developmental Immunology [Internet].  2013 [cited 2013 Oct 19];2013, Article ID 945945, doi:10.1155/2013/945945. Available from:
3 American College of Rheumatology (ACR). Biologics may prevent premature death in people with rheumatoid arthritis, study suggests. ScienceDaily [Internet] 2012 Nov 11 [cited 2013 Oct 19]. Available from:

Kelly O'Neill

Kelly O'Neill (formerly Kelly Young) has worked about 12 years as an advocate helping patients to be better informed and have a greater voice in their healthcare. She is the author of the best-selling book Rheumatoid Arthritis Unmasked: 10 Dangers of Rheumatoid Disease. Kelly received national acknowledgement with the 2011 WebMD Health Hero award. She is the president of the Rheumatoid Patient Foundation. Through her writing and speaking, she builds a more accurate awareness of rheumatoid disease (RD) aka rheumatoid arthritis (RA) geared toward the public and medical community; creates ways to empower patients to advocate for improved diagnosis and treatment; and brings recognition and visibility to the RA patient journey. In addition to RA Warrior, she writes periodically for newsletters, magazines, and websites. There are over 60,000 connections of her highly interactive Facebook page. You can also connect with Kelly on Twitter or YouTube, or LinkedIn. She created the hashtag: #rheum. Kelly is a mother of five, longtime home-schooler, NASA enthusiast, and NFL fan. She has lived over fourteen years with unrelenting RD. See also https:/

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5 thoughts on “Triple Therapy / Combination Therapy for Rheumatoid Arthritis

  • October 29, 2013 at 12:05 pm

    I keep reading about various treatments, but what if you have had an allergic reaction to MTX & Humira. Now i can’t take either of these – Have there been any studies done using something else entirely?

  • October 29, 2013 at 6:33 pm

    One thing that didn’t seem to be measured or compared was the amount of time suffering until a treatment began to work. bDMARDS can work rapidly- but triple therapy can take awhile. In the extra months it can take triple therapy to work, a patient can not only be in severe unremitting pain, but lose their job and put strain on family and finances.

    So even if, at the end of 6 months or a year, the treatments are equal; how can the horrible pain and suffering until that time be ignored? How can this not be measured? This trial really made me angry- to think of the pain endured and the lives forever changed- because somehow suffering for several months is ok if the end result is the same? I don’t think so!

  • October 29, 2013 at 6:43 pm

    I’d also like to add that 24 weeks can seem like a heck of a long time. They should be measuring this at 2 and 4 and 6 weeks…. I believe that TT would not hold a candle to bDMARDS. A better trial would be to get the RA under control ASAP with bDMARDS and only then to initiate a double randomized placebo trial with TT & bDMARDS. Then if the RA stays controlled either way it would make sense. Of course it takes actual understanding of the suffering involved to realize that an extra 20 weeks of severe pain is not humane.

  • October 29, 2013 at 10:42 pm

    I tried triple therapy before I went on to biologics. I really hoped that the lower cost, lower tech medications alone would be effective for me. Unfortunately, they weren’t. Now I’m on my 4th biologic in conjunction w/methotrexate and plaquenil. It’s great that triple therapy works for some, though.

  • November 9, 2013 at 1:04 pm

    The HAQ looks comparable but to me the Sharp score,erosions and joint space narrowing look worse. Do you think so?
    The main reason I wanted to take biologics was the sense of well being but a close second was the better effect on bones. That was the info I found 6 years ago. I felt really unhappy to find out that damage could progress on methotrexate.

    My husband thinks your picture is the shadow of a branch. To me it looks like two little bird feet sticking up


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